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Objective:To develop a novel animal model of sporadic amyotrophic lateral sclerosis (ALS), via intrathecal delivery of cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients into mice.
Background: ALS is a progressive neurodegenerative disorder characterized by motor neuron death. Only 10% of ALS patients have familial ALS, while the majority are afflicted with sporadic ALS. In most existing genetic rodent models of ALS, an observable disease phenotype takes a relatively long period of time (months) to develop. Here, we investigated whether pathological factors are present in the CSF of the sporadic form of ALS and if this can be studied in an experimental model of the disease.
Design/Methods: CSF obtained from ALS patients was administered to mice intrathecally. Control mice were injected with saline, or CSF obtained from healthy individuals, as well as CSF from patients with other neurological disease (OND). Mice underwent a laminectomy at cervical levels 4 and 5, then 3μl of CSF was injected under the dura mater into the subarachnoid space. Forelimb motor deficits were assessed at 1 day post injection, then mice were perfused for histological analyses of the spinal cord.
Results: ALS CSF-injected mice exhibited significantly impaired forelimb function compared to controls. Increased death of motor neurons was revealed by a significantly fewer number of ChAT-positive motor neurons and increased activated-caspase3 staining in the cervical spinal cords of ALS CSF-injected mice. Mice injected with ALS CSF displayed evidence of reactive astrogliosis and microglial activation, as assessed by Iba-1 and GFAP immunostaining respectively. These pathological features were not seen in the control groups.
Conclusions: Intrathecal delivery of ALS CSF induces motor weakness and degeneration of motor neurons in the cervical spinal cord by 1 day post injection. Identification of the pathological factors present in ALS CSF that are responsible for this degenerative phenotype is an important next step.